For a patient with either allergic conjunctivitis or dry eye, life can be pretty uncomfortable. When a patient suffers from both conditions at once, things can be downright miserable. Based on the prevalence of the two diseases—each has an incidence of about 20 percent—an estimate would suggest that less than 4 percent of the population have both ocular allergy and dry eye. However, clinical experience shows that they co-manifest much more frequently. The intersection of allergy, the environment and dry eye produces ocular surface inflammation, leading to a common pathway, making the response to either condition all the worse and complicating diagnosis and therapy. In this article, we'll take a look at how this intersection occurs and what you can do to treat it.

 


The Two Offenders


Allergic conjunctivitis is purported to afflict about a fifth of the general population. It's characterized by ocular itching and redness, swelling, tearing and chemosis, and is the result of antigen-induced IgE binding and subsequent mast cell activation. Prevailing hypotheses regarding its increasing prevalence range from more accurate diagnosis to overly enthusiastic hygiene to pollution. Though histamine is the primary mediator, a myriad of others, including eosinophil cationic protein (ECP), tryptase, platelet activating factor (PAF), heparin and various prostaglandins and interleukins, prolong and exacerbate the allergic reaction.


Dry eye is thought to occur in some 11 to 22 percent of people.1 Ocular burning is the primary symptom, while the signs are staining, reduced tear meniscus, gritty foreign body sensation, keratitis and (rarely) photophobia. It's caused by deficiencies or alterations in any of the components of the tear film, with underlying autoimmune, inflammatory, bacterial and environmental etiologies. Certain visual tasks, such as working on a computer, strain the eyes and reduce the blink rate, thereby depriving the ocular surface of the blink's tear film-replenishing effects.

 


Irritating Air


The possible effects of pollution and hygiene on the development of allergies continue to be investigated, long after David P. Strachan's proposal of the hygiene hypothesis.2 The irritants that constitute air pollution include hydrocarbons and aromatic compounds, such as those spewed by coal-burning factories and combustion engines, particularly those that use diesel fuel. Hydrocarbons can instigate oxidative stress and some aromatic compounds, particularly polycyclic aromatic hydrocarbons,3 are classified as carcinogens by the Environmental Protection Agency; their release within vehicle exhaust is carefully regulated. Irritants have traditionally been classified separately from allergens, as they don't provoke the IgE-mediated response the way that allergens do.

 


Union
of Irritants and Allergens


Classifying irritants separately, though, doesn't preclude the ability of pollutants to evoke an inflammatory response or exacerbate the allergic reaction. Scanning electron microscope images of pollen grains illustrated that the grains, once exposed to polluted air, develop an altered surface morphology and burst prematurely, releasing their protein constituents. When injected into mice, polluted pollen extracts were correlated with increased eosinophil and total IgE levels in comparison to mice injected with saline or non-polluted pollen.4 These results echoed previous findings, both in mice5 and in humans.6


Diesel exhaust particles, which are a conglomeration of various toxic compounds, may induce sensitization in atopic patients who were previously non-reactive to the specific allergens.7 Nitric oxide, one of the by-products of combustion engines, and sunlight can react to form low-level ozone, a reactive oxygen species (ROS) that can elicit oxidative stress and apoptosis. Endogenous enzymes known as glutathione-S-transferases (GSTs) metabolize ROS; however, when ROS occur in excess the safety system is overwhelmed, and the allergic response is enhanced. Furthermore, genetic polymorphisms of GSTs are relatively common, and null variants can diminish the individual's ability to metabolize ROS.8


It's hypothesized that ROS-induced alteration of the ocular surface may result in a diminished tear-film barrier to allergen penetration, thereby lowering the threshold at which an individual may display an allergic reaction. Compromised tear films can lead to dry-eye symptoms; as the tear film's barrier, diluent and eye wash functionalities are minimized; protection against pollen penetration is also diminished. The ocular allergic reaction can then be prolonged, leading to an allergy/environment/dry-eye cycle.

 


Allergic Dry Eyes


While allergic conjunctivitis is highly variable in severity, the specific offending allergens can typically be identified via skin tests. Dry eye, on the other hand, is typically intermittent, and manifestation depends on a multitude of genetic and environmental factors. For example, a given patient may only experience signs and symptoms when using a computer whose monitor is at a certain angle and when an overhead air conditioner is blowing dry air late at night. Dry eye is also exacerbated by the use of systemic antihistamines, hormonal imbalances that alter the blink rate and autoimmune conditions that limit the functionality of the lacrimal gland. The clear interaction of allergy, dry eye and environmental irritants makes untangling their etiology in prevalence studies difficult.



Just as many factors can instigate dry eye, ocular allergy is the result of a multitude of complex and highly individual genetic and environmental interactions, producing signs and symptoms that range from intermittently bothersome to persistently unbearable. Within this range of severity, the overall and relative quantities of allergic mediators vary widely. Seasonal allergic conjunctivitis is primarily characterized by histamine, and tear collections and conjunctival scrapings inconsistently reveal eosinophils. In contrast, more severe, persistent ocular allergy involves a late-phase response that augments the early-phase histamine release with a more readily noticeable release of ECP and pro-inflammatory mediators. Eosinophils, neutrophils, basophils and T lymphocytes are called to the scene and extravasate from blood vessels, resulting in swelling and inflammation. These cells also release histamine-releasing factors (HRFs) that serve to perpetuate the allergic cycle.9


Atopic keratoconjunctivitis and vernal keratoconjunctivitis are intense manifestations of ocular allergy, and research into their cellular profiles has revealed a counterintuitive link between allergy and dry eye. An allergy-related increase and alteration in the quality and quantity of aqueous production can translate to altered lipid and mucin components as well. The resulting unbalanced tear film produces inadequate barrier protection. The underlying component of these signs is ocular surface inflammation.


AKC is essentially an intense ocular extension of allergic dermatitis, characterized by corneal ulcerations and neovascularization, with the eyelids often being involved in the allergic reaction. VKC is a recurrent chronic disease that predominantly affects male children. Symptoms and signs include severe, persistent itching, giant tarsal papillae and limbal infiltrates. Researchers and physicians have noted that many patients with AKC and VKC also complain of dry-eye symptomatology, which includes foreign body sensation, burning and irritation. One study, which used both AKC and VKC patients, noted that all patients had tear film breakup times (BUT) of less than 10 seconds. AKC patients in particular had mean BUT values of approximately three seconds, and the BUT of VKC patients was approximately five seconds,10 both evidence of an unstable tear film.11 Schirmer values revealed VKC patients to have higher tear volumes than normal control patients, while AKC patients had lower tear volumes.10 But as evidenced by the breakup time, it's not the volume that should be focused on, but the quality of the tears.


In the study, AKC and VKC patients also had higher fluorescein/
rose bengal staining scores and lower corneal sensitivity readings.10 Chronic inflammation results in decreased corneal sensitivity, which plays into the neural loop, where blink rate and the lacrimal glands are linked together to maintain ocular surface homeostasis. When the neural input from the ocular surface is disrupted by inflammation, signaling is hindered and the tear film volume suffers, with an adverse effect on surface integrity.


Conjunctival goblet cells secrete mucus, which is spread over the corneal surface by blinking, where it enhances the spread and stability of the tear film while lubricating and hydrating the epithelium. Mucus production seems to be dependent on Th2 associated cytokines, including IL-9 and IL-13.12 Goblet cells undergo apoptosis during inflammatory conditions; goblet cell densities less than 1,000 cells/mm^2 are associated with severe ocular surface disease.13 Not surprisingly, AKC patients in particular have goblet cell counts indicative of ocular surface disease. In contrast, MUC 1, 2, and 4 mRNA expression is increased in AKC patients, while the expression of MUC4AC mRNA is significantly downregulated. As the upregulation of mucins wasn't associated with better tear-film stability, it's probably a defense mechanism against ocular surface disease and corneal ulcers.10


These results echoed findings in other AKC patients, where mean corneal sensitivity and BUT values were significantly lower than normals, inflammatory cells were present in higher numbers, and MUC 1, 2, and 4 mRNA expression was increased.12 It's important to recognize, however, that in both of these studies, ethics review boards would not permit washout periods prior to enrollment of active severe allergy patients. Most patients used systemic or topical steroids and antihistamines within two weeks of study initiation.


Another study,14 conducted in SAC patients, allowed a two-week washout period for both systemic and topical steroids and mast-cell stabilizers. Most surprisingly, this study of 39 patients showed SAC patients had a mean BUT of 3.4 ±1.5 seconds, compared with 12.4 ±2.4 seconds in the controls. Fluorescein staining was negative for all patients, and differences in Schirmer tests were insignificant. As judged by interferometry, lipid layer thickness was elevated in 78 percent of SAC patients. No patient had aqueous deficient dry eye; all SAC patients had tear instabilities with BUT-type deficiencies. Lipid layer thickness was negatively correlated with BUT scores, in that shorter BUTs corresponded with thicker lipid layers. It's possible that decreased tear film stability results from release of allergic mediators by inflammatory cells into the tear film, alteration of meibomian secretions by allergic inflammation and alteration in goblet cell numbers or mucin quantity or quality. Increased lipid layer thickness is likely a compensatory mechanism for increased tear evaporation. This altered tear film composition may account for the foreign body sensation, which is rarely reported by SAC patients but commonly reported by dry-eye patients.14 The reports of burning in allergy patients may suggest that they're being affected by a combined mechanism involving both allergic and dry-eye pathology.


Since these patients don't present with all the signs of dry eye—decreased tear volume, staining and BUT—they're frequently left undiagnosed. The unhealthy ocular surface is undeniable, as the shortened BUT of ocular allergy patients is likely the result of the inflammatory process and histamine activation, which compromise the conjunctival epithelium and disrupt goblet cell function.15,16 Patients may benefit from the addition of a tear substitute or a low-dose steroid to a regimen of a topical antihistamine/mast-cell stabilizer.16



It's reasonable to state that any pathology that causes alterations in ocular surface or tear-film physiology can disrupt the tear film. The ocular allergic pathology involves gene/molecular/environmental interactions that may be as individual to the patient as his or her fingerprints. The environmental and biological influences of dry eye are similarly unique to each patient. In many patients, it's clear that they have either seasonal allergic conjunctivitis, or that they have a particular variant of dry eye and their environmental urban irritant exposure is a cause of their ocular surface problems. It's increasingly apparent that these conditions can be interdependent. The common changes in the ocular surface include structural modifications in the epithelial cells, inflammatory cell infiltration and inflammatory mediator release, alteration in mucins by the affected goblet cells, and alterations in lipids by the affected meibomian glands. There are also often dramatic increases or decreases in the aqueous.


All of these variations from the normal ocular surface homeostasis lead to increased symptoms and ocular surface barrier breakdown, creating chronic inflammation. The use of antihistamine/mast-cell stabilizers and tear substitutes, along with the appropriate use of steroids such as loteprednol, should provide relief from this allergy/environment/dry-eye cycle. Monitoring of patients in order to adjust medication as needed, and patient education on the awareness and avoidance of the three P's—pollens, pollutants and parched environments—will improve patients' lives.

 

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Ms. Lilyestrom is managing editor at ORA Clinical Research in North Andover.

 

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